Impact of TRAIL on the immune system in peritonitis
Final Report Abstract
Peritonitis with consequent sepsis remains a common cause of death in surgical intensive care units to this day. Sepsis in this context represents an immunological failure in the interplay between the innate and acquired immune responses, ultimately leading to non-targeted destruction of the body's own tissue and consequently organ failure. Neutrophilic granulocytes are early effector cells in peritonitis. However, as sepsis progresses, their actions become indiscriminate. Simultaneously, the lifespan of these cells is extended during sepsis, primarily due to apoptosis inhibition. In previous work, we demonstrated that TRAIL (TNF-related apoptosis-inducing ligand) enhances survival in the Colon Ascendens Stent Peritonitis (CASP) model. Concurrently, more apoptotic neutrophilic granulocytes are observed during the course of sepsis under TRAIL therapy. We have now shown that the quantity and maturation of neutrophilic granulocytes within the first six hours of peritonitis are organ-dependent. While granulocytes derived from healthy animals do not respond to TRAIL stimulation with apoptosis, this changes early in the course of sepsis. This is accompanied by increased expression of the anti-apoptotic proteins Flip, c-IAP1, and McL1, as well as decreased expression of Bax. Simultaneously, the expression of both TRAIL and its receptors increases during the progression of sepsis. This indicates that the regulation of TRAIL-induced apoptosis is a mechanism through which neutrophilic granulocytes can modulate their lifespan during sepsis. In addition to neutrophilic granulocytes, T cells play a crucial role in the pathophysiology of sepsis. Here, we found reduced proliferation of TRAIL-deficient T lymphocytes, which can be restored by administering TRAIL. At the same time, TRAIL-deficient regulatory CD4 cells exhibited diminished suppressive capacity. In summary, significant influences of TRAIL on both the innate and adaptive immune systems are evident in peritonitis. These effects are partially contradictory and may thus potentially limit the clinical application of TRAIL.
Publications
-
Interactions of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer. Cancers, 11(8), 1161.
Beyer, Katharina; Baukloh, Ann-Kathrin; Stoyanova, Ani; Kamphues, Carsten; Sattler, Arne & Kotsch, Katja
-
Immune Phenotypic Characterization of a TRAIL-Knockout Mouse. Cancers, 15(5), 1475.
Stoyanova, Ani K.; Sattler, Arne; Hahn, Elisabeth M.; Hering, Nina A.; Arndt, Marco; Lauscher, Johannes Christian; Speichinger-Hillenberg, Fiona; Kotsch, Katja; Berg, Ann-Kathrin & Beyer, Katharina
-
The Impact of TRAIL on the Immunological Milieu during the Early Stage of Abdominal Sepsis. Cancers, 15(6), 1773.
Berg, Ann-Kathrin; Hahn, Elisabeth M.; Speichinger-Hillenberg, Fiona; Grube, Annemaria Silvana; Hering, Nina A.; Stoyanova, Ani K. & Beyer, Katharina
